The female sex steroid, progesterone, plays a central role in mammalian pregnancy by regulating crucial events in the uterus such as transformation of endometrium for implantation and maintenance of pregnancy. The hormone acts through its specific nuclear receptor and modulates the functions of target cells by controlling the synthesis of specific proteins. The identity of genes that are regulated by progesterone in the uterus during various phases of pregnancy, however, remains largely unknown. In this study, we employed a differential gene-screening method to identify the gene encoding ferritin heavy chain (FHC), a component of the multisubunit iron-binding protein ferritin, as being regulated by progesterone in the uterus. We observed that uterine expression of the FHC messenger RNAs (mRNAs) rose dramatically at the onset of pregnancy, coincident with the surge of progesterone. FHC expression continued at this elevated level throughout gestation when the progesterone concentration remained high. At term, FHC expression declined sharply as the progesterone concentration dropped. We localized FHC proteins exclusively in uterine stromal cells, a major site of action of progesterone during pregnancy. Administration of mifepristone, an antiprogestin, during the early stages of pregnancy abolished both FHC mRNA and protein expression, clearly suggesting a primary role of progesterone in the regulation of this gene. Consistent with this scenario, administration of progesterone to ovariectomized animals after a brief estrogen priming led to a marked (25-fold) induction of FHC mRNA in the uterus, whereas estrogen, dexamethasone, or dihydrotestosterone had no effect. Based on these results, we propose that FHC is a novel and useful marker to study progesterone-regulated events in the uterus during pregnancy.
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